Methods of forming 4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol esters and methods of using the same

ABSTRACT

Methods include formation of 4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol esters. The method comprises contacting a 1-chloro-3-fluoro-2-substituted benzene with an alkyl lithium to form a lithiated 1-chloro-3-fluoro-2-substituted benzene. The lithiated 1-chloro-3-fluoro-2-substituted benzene is contacted with an electrophilic boronic acid derivative to form a 4-chloro-2-fluoro-3-substituted-phenylboronate. The 4-chloro-2-fluoro-3-substituted-phenylboronate is reacted with an aqueous base to form a (4-chloro-2-fluoro-3-substituted-phenyl)trihydroxyborate. The (4-chloro-2-fluoro-3-substituted-phenyl)trihydroxyborate is reacted with an acid to form a 4 chloro-2-fluoro-3-substituted-phenylboronic acid. The 4-chloro-2-fluoro-3-substituted-phenylboronic acid is reacted with 2,3-dimethyl-2,3-butanediol to form 4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol esters . Methods of using 4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol esters to produce 6-(4-chloro-2-fluoro-3-substituted-phenyl)-4-aminopicolinates are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.13/722,471, filed Dec. 20, 2012, pending, which application claims thebenefit of U.S. Provisional Patent Application Ser. No. 61/582,173,filed Dec. 30, 2011, the disclosure of each of which is herebyincorporated herein in its entirety by this reference.

TECHNICAL FIELD

Embodiments of the present disclosure relate to methods of forming4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol esters and tomethods of using 4-chloro-2-fluoro-3-substituted-phenylboronic acidpinacol esters. Embodiments of the present disclosure also relate tomethods of forming2-(4-chloro-2-fluoro-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(PBE-pinacol), and to methods of using the same.

BACKGROUND

4-chloro-2-fluoro-3-methoxyphenylboronic acid (PBA) and2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (PBE) areuseful intermediates in the preparation of 6-(poly-substitutedaryl)-4-aminopicolinate compounds and 2-(poly-substitutedaryl)-6-amino-4-pyrimidinecarboxylic acid compounds, which are useful asherbicides. PBA may be esterified using 1,3-propanediol to form PBE.

For some operations it would be desirable to be able to efficientlycrystallize a 4-chloro-2-fluoro-substituted-phenylboronic acid, likePBA, or a 4-chloro-2-fluoro-3-substituted-phenylboronic acid ester, likePBE. For example, a 4-chloro-2-fluoro-3-substituted-phenylboronic acidester crystalline solid may be more convenient to store and transportthan a 4-chloro-2-fluoro-3-substituted-phenylboronic acid estersolution. Disadvantageously, PBE has a relatively low melting point,which may impair or preclude an efficient crystallization thereof. ThePBE melting point is 39-41° C. A need thus remains for a4-chloro-2-fluoro-3-substituted-phenylboronic acid ester that has arelatively higher melting point and that can be efficiently formed andefficiently used in subsequent processes, such as the production ofherbicide intermediates.

BRIEF SUMMARY

An embodiment of the present disclosure includes a method of forming a4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol ester thatcomprises contacting a 1-chloro-3-fluoro-2-substituted benzene with analkyl lithium to form a lithiated 1-chloro-3-fluoro-2-substitutedbenzene. The lithiated 1-chloro-3-fluoro-2-substituted benzene may becontacted with an electrophilic boronic acid derivative to form a4-chloro-2-fluoro-3-substituted-phenylboronate. The4-chloro-2-fluoro-3-substituted-phenylboronate may be reacted with anaqueous base to form a(4-chloro-2-fluoro-3-substituted-phenyl)trihydroxyborate. The(4-chloro-2-fluoro-3-substituted-phenyl)trihydroxyborate may be reactedwith an acid to form a 4 chloro-2-fluoro-3-substituted-phenylboronicacid. The 4-chloro-2-fluoro-3-substituted-phenylboronic acid may bereacted with 2,3-dimethyl-2,3-butanediol.

Another embodiment of the present disclosure includes a method offorming2-(4-chloro-2-fluro-3-methoxylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanethat comprises contacting 2-chloro-6-fluoroanisole with n-butyl lithiumto form 6-chloro-2-fluoro-3-lithioanisole. The6-chloro-2-fluoro-3-lithioanisole may be contacted with trimethyl borateto form dimethyl 4-chloro-2-fluoro-3-methoxyphenylboronate. The dimethyl4-chloro-2-fluoro-3-methoxyphenylboronate may be reacted with aqueouspotassium hydroxide to form potassium(4-chloro-2-fluoro-3-methoxyphenyl)trihydroxyborate. The potassium(4-chloro-2-fluoro-3-methoxyphenyl)trihydroxyborate then may be reactedwith aqueous hydrochloric acid to form4-chloro-2-fluoro-3-methoxyphenylboronic acid. The4-chloro-2-fluoro-3-methoxyphenylboronic acid may be reacted with2,3-dimethyl-2,3-butanediol.

Yet another embodiment of the present disclosure includes a method ofusing a 4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol estercomprising reacting the 4-chloro-2-fluoro-3-substituted-phenylboronicacid pinacol ester with methyl 4-acetamido-3,6-dichloropicolinate toproduce a 6-(4-chloro-2-fluoro-3-substituted-phenyl)-4-aminopicolinate.

Yet still another embodiment of the present disclosure includes a4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol esterproduced by introducing 2,3-dimethyl-2,3-butanediol into a solutioncomprising a 4-chloro-2-fluoro-3-substituted-phenylboronic acid, whereinthe 4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol ester isobtained at a yield of greater than approximately 90%.

DETAILED DESCRIPTION

Methods of forming 4-chloro-2-fluoro-3-substituted-phenylboronic acidpinacol esters, such as PBE-pinacol are disclosed, as well as methods ofusing the 4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacolesters. A 1-chloro-3-fluoro-2-substituted benzene may be reacted with analkyl lithium and an electrophilic boronic acid derivative to form a4-chloro-2-fluoro-3-substituted-phenylboronate. The4-chloro-2-fluoro-3-substituted-phenylboronate may be converted to a4-chloro-2-fluoro-3-substituted-phenylboronic acid by treatment with anaqueous base followed by acidification. The4-chloro-2-fluoro-3-substituted-phenylboronic acid may be condensed with2,3-dimethyl-2,3-butanediol (pinacol) to form the4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol ester. The4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol ester may beused in further reactions, such as a Suzuki coupling reaction, toproduce additional chemical compounds, such as6-(4-chloro-2-fluoro-3-substituted-phenyl)-4-aminopicolinates.

A reaction scheme for the preparation of a4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol ester from a1-chloro-3-fluoro-2-substituted benzene is shown below:

where X is F, OR₁, or NR₂R₃, Y is H or F, each of R₁, R₂, and R₃ isindependently a methyl group, an ethyl group, a propyl group, or a butylgroup. The reaction scheme is described in detail below.

An alkyl lithium may be added or introduced to the1-chloro-3-fluoro-2-substituted benzene to facilitate a lithiationreaction between the 1-chloro-3-fluoro-2-substituted benzene and thealkyl lithium and form a reaction mixture including a lithiated1-chloro-3-fluoro-2-substituted benzene. In at least some embodiments,the 1-chloro-3-fluoro-2-substituted benzene is 2-chloro-6-fluoroanisole(2,6-CFA). 1-chloro-3-fluoro-2-substituted benzenes may be produced byconventional techniques, which are not described in detail herein. Thealkyl lithium may be any compound that includes a lithium and an alkylfunctional group (i.e., of straight chain, branched chain, or cyclicconfiguration), such as methyl, ethyl, 1-methylethyl, propyl,cyclopropyl, butyl, 1,1-dimethylethyl, cyclobutyl, 1-methylpropyl, orhexyl. By means of non-limiting example, the alkyl lithium may includemethyl lithium, n-butyl lithium (n-BuLi), s-butyl lithium, t-butyllithium, or propyl lithium. In one or more embodiments, the alkyllithium is n-BuLi. Alkyl lithiums are commercially available fromnumerous sources, including but not limited to, Sigma-Aldrich Co. (St.Louis, MO). In embodiments where the 1-chloro-3-fluoro-2-substitutedbenzene is 2,6-CFA and the alkyl lithium is n-BuLi, the lithiated1-chloro-3-fluoro-2-substituted benzene may be6-chloro-2-fluoro-3-lithioanisole (Li-2,6-CFA).

The lithiation reaction may be conducted in an inert organic solvent inwhich the 1-chloro-3-fluoro-2-substituted benzene is at least partiallysoluble. In one or more embodiments, the 1-chloro-3-fluoro-2-substitutedbenzene is at least substantially dissolved in the inert organicsolvent. The inert organic solvent may include, but is not limited to, aC₅-C₈ hydrocarbon (i.e., of straight-chain, branched, or cyclicconfiguration), such as a pentane, a hexane, a cyclohexane, aniso-octane, an ether (e.g., diethyl ether, tetrahydrofuran, dioxane,glycol ethers including 1,2-dimethoxyethane), or combinations thereof.In at least some embodiments, the inert organic solvent is1,2-dimethoxyethane (DME).

At least one molar equivalent of the alkyl lithium may be used relativeto the 1-chloro-3-fluoro-2-substituted benzene. The alkyl lithium may beadded in a slight excess relative to the 1-chloro-3-fluoro-2-substitutedbenzene compound, such as from about 1% to about 10% molar excessrelative to the 1-chloro-3-fluoro-2-substituted benzene, or from about2% to about 5% molar excess relative to the1-chloro-3-fluoro-2-substituted benzene. The lithiation reaction may beconducted under anhydrous conditions, at atmospheric pressure orgreater, and at a temperature of less than or equal to about −30° C.,preferably less than −50° C., such as less than about −65° C. Thereaction mixture may be agitated (e.g., via stirring, ultrasonicallyagitating, shaking a containment vessel) for a sufficient amount of timeto facilitate the deprotonation of the 1-chloro-3-fluoro-2-substitutedbenzene at a position (C4) between a carbon atom (C3) to which thefluoro substituent is bonded and another carbon atom (C5) to which the Ygroup is bonded. The lithiation reaction may be conducted under an inertatmosphere, such as under a nitrogen (N₂) atmosphere.

An electrophilic boronic acid derivative may be added or introduced tothe reaction mixture to react with or contact the lithiated1-chloro-3-fluoro-2-substituted benzene and form a phenyl boronatesolution including a 4-chloro-2-fluoro-3-substituted-phenylboronate. Theelectrophilic boronic acid derivative may be a trialkyl borate, such astrimethyl borate (B(OMe)₃), triethyl borate (B(OEt)₃), or triisopropylborate (B(Oi-Pr)₃). In at least some embodiments, the electrophilicboronic acid derivative is B(OMe)₃. In embodiments in which theelectrophilic boronic acid derivative is B(OMe)₃ and the lithiated1-chloro-3-fluoro-2-substituted benzene is Li-2,6-CFA, the4-chloro-2-fluoro-3-substituted-phenylboronate may be dimethyl4-chloro-2-fluoro-3-methoxyphenylboronate (PBA-diMe). The electrophilicboronic acid derivative may be added slowly, while maintaining atemperature of the reaction mixture of less than or equal to −30° C.,preferably less than −50° C., such as less than about −65° C. Thereaction mixture may be agitated for an amount of time sufficient forthe electrophilic boronic acid derivative to react with lithiated1-chloro-3-fluoro-2-substituted benzene. By the end of the reaction thesalinated phenyl boronate solution may have a temperature within a rangeof from about 20° C. to about 25° C. (e.g., ambient temperature).

An aqueous base may be added or introduced to the phenyl boronatesolution to react with or hydrolyze the4-chloro-2-fluoro-3-substituted-phenylboronate and form a firstmulti-phase solution including a(4-chloro-2-fluoro-3-substituted-phenyl)trihydroxyborate. The aqueousbase may include a base of sufficient strength to hydrolyze the4-chloro-2-fluoro-3-substituted-phenylboronate. By means of non-limitingexample, the aqueous base may include potassium hydroxide (KOH), sodiumhydroxide (NaOH), or combinations thereof. In at least some embodiments,the aqueous base is aqueous KOH. In embodiments where the4-chloro-2-fluoro-3-substituted-phenylboronate is PBA-diMe and theaqueous base is KOH, the(4-chloro-2-fluoro-3-substituted-phenyl)trihydroxyborate may bepotassium (4-chloro-2-fluoro-3-methoxyphenyl) trihydroxyborate (PBA-K).Adding or introducing the aqueous base to the phenyl boronate solutionmay yield a first multi-phase solution having a greater temperature thanthe phenyl boronate solution. Optionally, a cooling means (e.g., a waterbath for the reaction vessel) may be provided to control a temperatureof the first multi-phase solution, such that the temperature remainswithin a range of from about 25° C. to about 30° C. The firstmulti-phase solution may be agitated for a sufficient amount of time forthe aqueous base to hydrolyze the4-chloro-2-fluoro-3-substituted-phenylboronate. The first multi-phasesolution may then be separated into a first organic phase and a firstaqueous phase (e.g., by transferring the first multi-phase solution intoa separation vessel, such as a separatory funnel). The first organicphase may be discarded, while the first aqueous phase, which includesthe (4-chloro-2-fluoro-3-substituted-phenyl)trihydroxyborate, may befurther treated, as described in detail below.

At least one acid may be added or introduced to the first aqueous phaseto react with or protonate the(4-chloro-2-fluoro-3-substituted-phenyl)trihydroxyborate and form aphenyl boronic acid solution including a4-chloro-2-fluoro-3-substituted-phenylboronic acid. By means ofnon-limiting example, the at least one acid may include hydrochloricacid (HCl). Other acids include hydrobromic acid (HBr), sulfuric acid(H₂SO₄), methane sulfonic acid and para-toluene sulfonic acid. The atleast one acid may be used neat or may be diluted with a solvent. In atleast some embodiments, the acid is 6M aqueous HCl. An equimolar amountor an excess amount of the at least one acid relative to the(4-chloro-2-fluoro-3-substituted-phenyl)trihydroxyborate may be used. Inembodiments where the(4-chloro-2-fluoro-3-substituted-phenyl)trihydroxyborate is PBA-K, the4-chloro-2-fluoro-3-substituted-phenylboronic acid formed may be4-chloro-2-fluoro-3-methoxyphenylboronic acid (PBA). Optionally, acooling means may be provided to control the temperature of the phenylboronic acid solution such that the temperature remains within a rangeof from about 25° C. to about 30° C. The phenyl boronic acid solutionmay be agitated for a sufficient amount of time to enable a substantialconversion of the(4-chloro-2-fluoro-3-substituted-phenyl)trihydroxyborate to the4-chloro-2-fluoro-3-substituted-phenylboronic acid.

A water miscible solvent may be added or introduced to the phenylboronic acid solution to form a second multi-phase solution. The4-chloro-2-fluoro-3-substituted-phenylboronic acid may be substantiallysoluble in the water miscible organic solvent relative to its solubilityin the phenyl boronic acid solution such that the second multi-phasesolution may have a second organic phase that includes the4-chloro-2-fluoro-3-substituted-phenylboronic acid and the watermiscible solvent. The second organic phase may also include the inertorganic solvent and water. The water miscible organic solvent may becompatible with subsequent reactions involving the4-chloro-2-fluoro-3-substituted-phenylboronic acid such that a solventexchange need not be conducted. By means of non-limiting example, thewater miscible solvent may be 4-methyl-2-pentanone (i.e., methylisobutyl ketone)(MIBK), acetonitrile (MeCN), ethyl acetate (EtOAc), orcombinations thereof. In a particular embodiment, toluene can also beused. In at least some embodiments, the water miscible solvent is MIBK.Optionally, a salt, such as potassium chloride (KCl), sodium chloride(NaCl), calcium chloride (CaCl₂), sodium bromide (NaBr), potassiumbromide (KBr), sodium sulfate (Na₂SO₄), ammonium chloride (NH₄Cl), orcombinations thereof, may be added or introduced to at least one of theaqueous phase of the first multi-phase solution, the phenyl boronic acidsolution, and the second multi-phase solution to minimize the amount ofwater in the second organic phase. The second organic phase may then beseparated from a second aqueous phase of the second multi-phase solution(e.g., via a separatory funnel). Optionally, the second organic phasemay be desolvated under reduced pressure or by crystallization toisolate the 4-chloro-2-fluoro-3-substituted-phenylboronic acid as asolid.

Pinacol may be added or introduced to the second organic phase or to asolution including the 4-chloro-2-fluoro-3-substituted-phenylboronicacid (e.g., a 4-chloro-2-fluoro-3-substituted-phenylboronic acidisolated as a solid and then dissolved in a solvent such as MIBK, MeCN,EtOAc, or combinations thereof) to facilitate a condensation reactionbetween the pinacol and the4-chloro-2-fluoro-3-substituted-phenylboronic acid and form a pinacolester solution including a 4-chloro-2-fluoro-3-substituted-phenylboronicacid pinacol ester. The pinacol may be used neat or in a water misciblesolvent, such as MIBK, MeCN, EtOAc, or combinations thereof. In at leastsome embodiments, the pinacol is solvated with MIBK. In embodimentswhere the 4-chloro-2-fluoro-3-substituted-phenylboronic acid is PBA, thecondensation reaction may form PBE-pinacol. The4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol ester mayremain in solution and may be used directly in subsequent reactionswithout additional concentration or drying. Optionally, the pinacolester solution may be desolvated under reduced pressure or bycrystallization to isolate the4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol ester as acrystalline solid.

The detailed reaction scheme below illustrates a representativeconversion of 2,6-CFA to PBE-pinacol:

2,6-CFA may be reacted with n-BuLi in anhydrous DME at a temperatureless than or equal to −30° C., preferably less than −50° C., such asless than about −65° C. to form the reaction mixture includingLi-2,6-CFA. B(OMe)₃ may be added or introduced to the reaction mixture,where it may contact the Li-2,6,CFA and form the phenyl boronatesolution including PBA-diMe. KOH in water may be added or introduced tothe phenyl boronate solution at ambient temperature to react with thePBA-diMe and form the first multi-phase solution including PBA-K. Afteragitation, the first aqueous and the first organic phase of the firstmulti-phase solution may be separated. The first aqueous phase, whichincludes the PBA-K, may be acidified with 6 M aqueous HCl and agitatedto form the phenyl boronic acid solution including PBA. MIBK may beadded or introduced to the phenyl boronic acid solution to form thesecond multi-phase solution having the second organic phase includingPBA, DME, and MIBK. The second organic phase may be separated andreacted with pinacol in MIBK to form the pinacol ester solutionincluding PBE-pinacol. A yield of the PBE-pinacol may be greater than orequal to about 90%, such as greater than or equal to about 95%.

The pinacol ester solution or a4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol estercrystalline solid, may be utilized in additional chemical reactions,such as a Suzuki coupling reaction. By means of non-limiting example,the pinacol ester solution (or the4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol estercrystalline solid) may undergo a cross-coupling reaction with methyl4-acetamido-3,6-dichloropicolinate (i.e., acetylated aminopyralid methylester)(AcAP-Me) to produce or form a6-(4-chloro-2-fluoro-3-substituted-phenyl)-4-aminopicolinate, such asmethyl4-acetamido-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate(Ac729-Me). PBE-pinacol may be used to produce2-(4-chloro-2-fluoro-3-methoxyphenyl)-6-amino-4-pyrimidinecarboxylicacid. The coupling partner to PBE-pinacol may be methyl6-acetamido-2-chloropyrimidine-4-carboxylate or its unprotected versionthe 6-amino-2-chloropyrimidine-4-carboxylic acid. The cross-couplingreaction may occur in the presence of a palladium catalyst, a ligand,and a base. In at least some embodiments, the palladium catalyst ispalladium(II)acetate (Pd(OAc)₂), the base is aqueous potassium carbonate(K₂CO₃), and the ligand is triphenylphosphine (PPh₃). The AcAP-Me may beused neat or may be provided in a solvent such as MIBK, MeCN, EtOAc,water, or combinations thereof.

The palladium catalyst, the ligand, and the base may be added to adeoxygenated mixture including the AcAP-Me and the pinacol estersolution (or the 4-chloro-2-fluoro-3-substituted-phenylboronic acidpinacol ester crystalline solid) to form a coupling reaction mixture.The coupling reaction mixture may be agitated at a temperature within arange of from about 40° C. to about 70° C. for a sufficient amount totime to complete a cross-coupling reaction and form a third multi-phasesolution having an third organic phase including the6-(4-chloro-2-fluoro-3-substituted-phenyl)-4-aminopicolinate. Thepalladium catalyst may be removed (e.g., by exposing the thirdmulti-phase solution to celite), and the third organic phase may beseparated or extracted. In embodiments where the coupling reactionmixture includes PBE-pinacol and AcAP-Me, a yield of Ac729-Me may begreater than about 85%, such as greater than about 87%, or greater thanabout 90%.

4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol esters may beformed at generally high yields (e.g., greater than or equal to 90%yield of PBE-pinacol), and may be used as intermediates to obtaingenerally high yields of desired products (e.g., greater than or equalto 85% yield of Ac729-Me). 4-chloro-2-fluoro-3-substituted-phenylboronicacid pinacol esters may also have relatively higher melting points(e.g., from about 61° C. to about 62° C. for PBE-pinacol), enabling theefficient isolation of 4-chloro-2-fluoro-3-substituted-phenylboronicacid pinacol esters as crystalline solids. Being able to isolate4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol esters ascrystalline solids enables the use of4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol esters inoperations where at least one of the storage, transportation, and use ofa 4-chloro-2-fluoro-3-substituted-phenylboronic acid ester solutionwould be inconvenient or unfavorable.

The following examples serve to explain embodiments of the presentdisclosure in more detail. These examples are not to be construed asbeing exhaustive or exclusive as to the scope of this invention.

EXAMPLES Example 1 Synthesis and Isolation of PBA

2,6-CFA (10.0 g, 62. 28 mmol) was weighed in a separate flask andtransferred to a 3-neck, 500-ml round bottom flask equipped with athermocouple temperature probe, stir bar, and a N₂ inlet. The flask wasrinsed with anhydrous DME. Additional DME was added to the reactionflask to give a total DME volume of 106 ml. The reaction was cooled to−78° C. with a dry ice/acetone bath. Once the reaction reached −77° C.,n-BuLi (29 ml, 71.62 mmol, 2.5 M in hexanes) was added slowly, dropwise,using a syringe pump over a 45 minute period. The highest temperaturereached during addition was −70.1° C. After complete addition of n-BuLi,the reaction was left to stir for 1 hour at −74.1° C. After 1 hour,B(OMe)₃ (10.5 ml, 93.42 mmol) was added dropwise using a syringe pumpover a period of 22 minutes. The highest temperature reached during theB(OMe)₃ addition was −67.0° C. After the complete addition of B(OMe)₃,the dry ice/acetone bath was removed and the reaction mixture warmed toroom temperature (about 23.1° C.). Once the reaction mixture reachedroom temperature, the reaction was left to stir an additional 1 hour atthat temperature. This procedure was repeated several times to generatea large amount of PBA-diMe in DME. 244.0 g of PBA-diMe in DME (10.3% PBAbasis), 27.82 g of 45% KOH, and 108.70 g of deionized water were addedto a one liter flask containing a magnetic stirrer. The one liter flaskwas cooled with a cold water bath to maintain a temperature of 25° C. to30° C. during the additions. The mixture was stirred for about 2 h andwas then vacuum filtered to remove lithium salts. Aqueous and organicphases of the mixture were then separated. Concentrated HCl (40.48 g)was added to the aqueous phase. The aqueous phase was cooled with a coldwater bath during the addition of the HCl to maintain a temperature of25° C. to 30° C. The aqueous phase was stirred for about 15 minutes toachieve complete dissolution. MIBK (35.91 g) was added to the aqueousphase and the aqueous phase was stirred for about 15 minutes. An organicphase separated from an aqueous phase to give 127.6 g of the organicphase. Analysis of the organic phase gave 17.57% by weight (89.1% yield)of PBA. The organic phase was concentrated to dryness and then placed ina vacuum oven at 50° C. to give a white solid.

Example 2 Formation of PBE-pinacol from PBA

PBA solid (3.0 g, 14.68 mmol) was added to a 100 mL round bottom flaskequipped with a magnetic stirrer and N₂ inlet. The PBA solid wasdissolved in EtOAc (35 mL) and pinacol (1.7 g, 14.7 mmol) was added. Themixture was stirred for 2 hours at room temperature (approximately 23.1°C.). After 2 hours the reaction was complete. The reaction mixture wasconcentrated under reduced pressure to give an oil that, when placed onhigh vacuum, gave a crystalline solid of PBE-pinacol in >99% yield. Aportion of the crystalline solid was purified using columnchromatography using a 8:1 Hexane/EtOAc ratio (v/v) to give aPBE-pinacol solid that had a melting point of 61° C. to 62° C.

Example 3 Use of PBE-pinacol to Produce an Herbicide Intermediate

PBE-pinacol (2.61 g, 9.12 mmol), acetylated aminopyralid methyl ester(2.0 g, 7.6 mmol), triphenyl phosphine (20 mg, 0.076 mmol), andpalladium(II) acetate (9 mg, 0.038 mmol) were added, under a N₂atmosphere, to a 50 mL 3-neck round bottom flask equipped with acondenser, thermocouple temperature probe, magnetic stir bar, and N₂inlet. The solvents, MIBK (10 mL) and MeCN (3.0 mL), were spargedseparately with N₂ for 30 minutes with stirring then added to thereaction flask. The reaction mixture was stirred for 5 minutes beforeadding an aqueous solution of K₂CO₃ (22.8%, 11.4 mL, 22.8 mmol,previously sparged for 30 minutes with N₂). The reaction mixture washeated to 60° C. and stirred for 2 hours. After 2 hours, the reactionwas sampled by GC to determine completion of the reaction. Once thereaction was complete, the mixture was transferred to a heatedseparatory funnel and the phases separated. The organic phase was sampleby GC with an internal standard (valerophenone) to yield 87% (2.53 g)Ac729-Me.

While the invention may be susceptible to various modifications andalternative forms, specific embodiments have been described by way ofexample in detail herein. However, it should be understood that theinvention is not intended to be limited to the particular formsdisclosed. Rather, the invention is to cover all modifications,equivalents, and alternatives falling within the scope of the inventionas defined by the following appended claims and their legal equivalents.

What is claimed is:
 1. A method of forming and using a4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol ester,comprising: contacting a 1-chloro-3-fluoro-2-substituted benzene with analkyl lithium to form a lithiated 1-chloro-3-fluoro-2-substitutedbenzene; contacting the lithiated 1-chloro-3-fluoro-2-substitutedbenzene with an electrophilic boronic acid derivative to form a4-chloro-2-fluoro-3-substituted-phenylboronate; reacting the4-chloro-2-fluoro-3-substituted-phenylboronate with an aqueous base toform a (4-chloro-2-fluoro-3-substituted-phenyl)trihydroxyborate;reacting the (4-chloro-2-fluoro-3-substituted-phenyl)trihydroxyboratewith an acid to form a 4-chloro-2-fluoro-3-substituted-phenylboronicacid; reacting the 4-chloro-2-fluoro-3-substituted-phenylboronic acidwith 2,3-dimethyl-2,3-butanediol to form a4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol ester; andsubjecting the 4-chloro-2-fluoro-3-substituted-phenylboronic acidpinacol ester to a Suzuki's coupling reaction in a medium consisting ofa Suzuki's coupling reactant, a palladium catalyst, a ligand, at leastone solvent, and a base, wherein the Suzuki's coupling reactant is amethyl 4-acetamido-3,6-dichloropicolinate to produce a6-(4-chloro-2-fluoro-3-substituted-phenyl)-4-aminopicolinate, or whereinthe Suzuki's coupling reactant is a methyl6-acetamido-2-chloropyrimidine-4-carboxylate or a6-amino-2-chloropyrimidine-4-carboxylic acid to produce a6-(4-chloro-2-fluoro-3-substituted-phenyl)-4-aminopicolinate.
 2. Themethod of claim 1, wherein reacting the4-chloro-2-fluoro-3-substituted-phenylboronic acid with2,3-dimethyl-2,3-butanediol comprises obtaining a yield of the4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol ester ofgreater than or equal to about 90%.
 3. The method of claim 1, whereincontacting the 1-chloro-3-fluoro-2-substituted benzene with the alkyllithium comprises introducing an alkyl lithium into a solutioncomprising the 1-chloro-3-fluoro-2-substituted benzene and an anhydroussolvent to form a reaction mixture comprising the lithiated1-chloro-3-fluoro-2-substituted benzene.
 4. The method of claim 3,wherein contacting the lithiated 1-chloro-3-fluoro-2-substituted benzenewith the electrophilic boronic acid derivative comprises adding theelectrophilic boronic acid derivative to the reaction mixture to form aphenyl boronate solution comprising the4-chloro-2-fluoro-3-substituted-phenylboronate.
 5. The method of claim4, wherein reacting the 4-chloro-2-fluoro-3-substituted-phenylboronatewith the aqueous base comprises adding the aqueous base to the phenylboronate solution to form a first multi-phase solution comprising afirst aqueous phase and a first organic phase, the first aqueous phasecomprising the (4-chloro-2-fluoro-3-substituted-phenyl)trihydroxyborate.6. The method of claim 5, wherein reacting the(4-chloro-2-fluoro-3-substituted-phenyl)trihydroxyborate with an acidcomprises: separating the first aqueous phase and the first organicphase; and adding the acid to the first aqueous phase to form a phenylboronic acid solution comprising the4-chloro-2-fluoro-3-substituted-phenylboronic acid.
 7. The method ofclaim 6, wherein reacting the4-chloro-2-fluoro-3-substituted-phenylboronic acid with the2,3-dimethyl-2,3-butanediol comprises: adding a water miscible solventto the phenyl boronic acid solution to form a second multi-phasesolution comprising a second aqueous phase and a second organic phase,the second organic phase comprising the4-chloro-2-fluoro-3-substituted-phenylboronic acid; separating thesecond aqueous phase and the second organic phase; and introducing the2,3-dimethyl-2,3-butanediol into the second organic phase to form apinacol ester solution comprising the4-chloro-2-fluoro-3-substituted-phenylboronic acid pinacol ester.
 8. Themethod of claim 7, wherein adding a water miscible solvent solution tothe phenyl boronic acid solution comprises adding at least one of4-methyl-2-pentanone, acetonitrile, and ethyl acetate to the phenylboronic acid solution.
 9. A method of forming and using2-(4-chloro-2-fluoro-3-methoxylphenyl)-4,4,5,5-tetramethy-1,3,2-dioxaborolane, comprising: contacting 2-chloro-6-fluoroanisolewith n-butyl lithium to form 6-chloro-2-fluoro-3-lithioanisole;contacting the 6-chloro-2-fluoro-3-lithioanisole with trimethyl borateto form dimethyl 4-chloro-2-fluoro-3-methoxyphenylboronate; reacting thedimethyl 4-chloro-2-fluoro-3-methoxyphenylboronate with aqueouspotassium hydroxide to form potassium(4-chloro-2-fluoro-3-methoxyphenyl)trihydroxyborate; reacting thepotassium (4-chloro-2-fluoro-3-methoxyphenyl)trihydroxyborate withaqueous hydrochloric acid to form4-chloro-2-fluoro-3-methoxyphenylboronic acid; reacting the4-chloro-2-fluoro-3-methoxyphenylboronic acid with2,3-dimethyl-2,3-butanediol to form a2-(4-chloro-2-fluoro-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane; and subjecting the2-(4-chloro-2-fluoro-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneto a Suzuki's coupling reaction in a medium consisting of a Suzuki'scoupling reactant, a palladium catalyst, a ligand, at least one solvent,and a base, wherein the Suzuki's coupling reactant comprises at leastone of methyl 4-acetamido-3,6-dichloropicolinate, methyl6-acetamido-2-chloropyrimidine-4-carboxylate, or6-amino-2-chloropyrimidine-4-carboxylic acid.
 10. The method of claim 9,wherein reacting the 4-chloro-2-fluoro-3-methoxyphenylboronic acid withthe 2,3-dimethyl-2,3-butanediol comprises obtaining a yield of the2-(4-chloro-2-fluoro-3-methoxylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneof greater than or equal to about 90%.
 11. The method of claim 9,wherein contacting the 2-chloro-6-fluoroanisole with the n-butyl lithiumcomprises introducing n-butyl lithium into a solution comprising the2-chloro-6-fluoroanisole and at least one of 1,2-dimethoxyethane,diethyl ether, tetrahydrofuran, and dioxane to form a reaction mixturecomprising the 6-chloro-2-fluoro-3-lithioanisole.
 12. The method ofclaim 11, wherein contacting the 6-chloro-2-fluoro-3-lithioanisole withthe trimethyl borate comprises adding the trimethyl borate to thereaction mixture to form a phenyl boronate solution comprising thedimethyl 4-chloro-2-fluoro-3-methoxyphenylboronate.
 13. The method ofclaim 12, wherein reacting the dimethyl4-chloro-2-fluoro-3-methoxyphenylboronate with the aqueous potassiumhydroxide comprises adding the aqueous potassium hydroxide to the phenylboronate solution to form a first multi-phase solution comprising afirst aqueous phase and a first organic phase, the first aqueous phasecomprising the potassium(4-chloro-2-fluoro-3-methoxyphenyl)trihydroxyborate.
 14. The method ofclaim 13, wherein reacting the potassium(4-chloro-2-fluoro-3-methoxyphenyl)trihydroxyborate with the aqueoushydrochloric acid comprises: separating the first aqueous phase and thefirst organic phase; and adding the aqueous hydrochloric acid to thefirst aqueous phase to form a phenyl boronic acid solution comprisingthe 4-chloro-2-fluoro-3-methoxyphenylboronic acid.
 15. The method ofclaim 14, wherein reacting the 4-chloro-2-fluoro-3-methoxyphenylboronicacid with the 2,3-dimethyl-2,3-butanediol comprises: adding at least oneof 4-methyl-2-pentanone, acetonitrile, and ethyl acetate to the phenylboronic acid solution to form a second multi-phase solution comprising asecond aqueous phase and a second organic phase, the second organicphase comprising the 4-chloro-2-fluoro-3-methoxyphenylboronic acid;separating the second aqueous phase and the second organic phase; andintroducing the 2,3-dimethyl-2,3-butanediol into the second organicphase to form a pinacol ester solution comprising the2-(4-chloro-2-fluoro-3-methoxylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.